NM_018706.7:c.1821C>G

Variant names:

• chr10-12101106-C-G
• rs2062988
• NM_018706.7:c.1821C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018706.7(DHTKD1):​c.1821C>G​(p.Ile607Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.799 in 1,613,602 control chromosomes in the GnomAD database, including 518,169 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I607V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.74 (42028 hom., cov: 31)
  • Exomes 𝑓: 0.81 (476141 hom.)
• Consequence: DHTKD1 NM_018706.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.27
• Publications: 35 publications found

Genes affected

DHTKD1 (HGNC:23537): (dehydrogenase E1 and transketolase domain containing 1) This gene encodes a component of a mitochondrial 2-oxoglutarate-dehydrogenase-complex-like protein involved in the degradation pathways of several amino acids, including lysine. Mutations in this gene are associated with 2-aminoadipic 2-oxoadipic aciduria and Charcot-Marie-Tooth Disease Type 2Q. [provided by RefSeq, May 2013]

DHTKD1 Gene-Disease associations (from GenCC):

• 2-aminoadipic 2-oxoadipic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Charcot-Marie-Tooth disease axonal type 2Q

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.599526E-7).
• BP6: Variant 10-12101106-C-G is Benign according to our data. Variant chr10-12101106-C-G is described in ClinVar as Benign. ClinVar VariationId is 1170352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018706.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHTKD1	NM_018706.7	MANE Select	c.1821C>G	p.Ile607Met	missense	Exon 10 of 17	NP_061176.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHTKD1	ENST00000263035.9	TSL:1 MANE Select	c.1821C>G	p.Ile607Met	missense	Exon 10 of 17	ENSP00000263035.4
	DHTKD1	ENST00000448829.1	TSL:5	c.474C>G	p.Ile158Met	missense	Exon 4 of 6	ENSP00000398482.1

Frequencies

GnomAD3 genomes AF: 0.738 AC: 112088 AN: 151868 Hom.: 41996 Cov.: 31

Gnomad AFR AF: 0.598

Gnomad AMI AF: 0.828

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.831

Gnomad EAS AF: 0.689

Gnomad SAS AF: 0.876

Gnomad FIN AF: 0.757

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.807

Gnomad OTH AF: 0.739

GnomAD2 exomes AF: 0.776 AC: 195068 AN: 251398 AF XY: 0.789

Gnomad AFR exome AF: 0.590

Gnomad AMR exome AF: 0.696

Gnomad ASJ exome AF: 0.828

Gnomad EAS exome AF: 0.683

Gnomad FIN exome AF: 0.750

Gnomad NFE exome AF: 0.813

Gnomad OTH exome AF: 0.790

GnomAD4 exome AF: 0.805 AC: 1177279 AN: 1461616 Hom.: 476141 Cov.: 46 AF XY: 0.809 AC XY: 588132 AN XY: 727152

African (AFR) AF: 0.592 AC: 19815 AN: 33470

American (AMR) AF: 0.699 AC: 31236 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.830 AC: 21688 AN: 26128

East Asian (EAS) AF: 0.702 AC: 27867 AN: 39694

South Asian (SAS) AF: 0.876 AC: 75517 AN: 86238

European-Finnish (FIN) AF: 0.758 AC: 40459 AN: 53402

Middle Eastern (MID) AF: 0.814 AC: 4696 AN: 5766

European-Non Finnish (NFE) AF: 0.817 AC: 908367 AN: 1111830

Other (OTH) AF: 0.789 AC: 47634 AN: 60382

GnomAD4 genome AF: 0.738 AC: 112166 AN: 151986 Hom.: 42028 Cov.: 31 AF XY: 0.739 AC XY: 54918 AN XY: 74290

African (AFR) AF: 0.598 AC: 24762 AN: 41436

American (AMR) AF: 0.742 AC: 11311 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.831 AC: 2885 AN: 3470

East Asian (EAS) AF: 0.689 AC: 3559 AN: 5166

South Asian (SAS) AF: 0.876 AC: 4222 AN: 4822

European-Finnish (FIN) AF: 0.757 AC: 7993 AN: 10556

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.807 AC: 54867 AN: 67978

Other (OTH) AF: 0.743 AC: 1571 AN: 2114

Alfa AF: 0.797 Hom.: 36270

Bravo AF: 0.725

TwinsUK AF: 0.826 AC: 3064

ALSPAC AF: 0.821 AC: 3166

ESP6500AA AF: 0.601 AC: 2649

ESP6500EA AF: 0.814 AC: 7002

ExAC AF: 0.779 AC: 94535

Asia WGS AF: 0.798 AC: 2775 AN: 3478

EpiCase AF: 0.819

EpiControl AF: 0.822

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 06, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

2-aminoadipic 2-oxoadipic aciduria Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Charcot-Marie-Tooth disease axonal type 2Q Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.022
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.26
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.095
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	7.6e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.88	N
PhyloP100		7.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	3.3	N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.097
MPC		0.12
ClinPred		0.018	T
GERP RS		5.5
Varity_R		0.28
gMVP		0.58
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2062988; hg19: chr10-12143105; COSMIC: COSV53803677; COSMIC: COSV53803677;